Our non-human primate studies have shown that a therapeutic vaccine, named DermaVir, could induce control of SIV and be beneficial for the survival of late-stage SIV-infected monkeys. In order to test the vaccine in human clinical trials, an HIV counterpart is needed, and the proper DNA component of DermaVir has to be constructed. However, the current construct, containing one genetic inactivation in the integrase region of the HIV genome, may not be safe enough to proceed to clinical use. This project proposes to improve the safety of the construct by introducing additional genetic modifications while retaining the efficacy of gene expression and immunogenicity. The project will have three aims: Specific Aim 1. Improve the safety of the HIV construct by a) removing the flanking human genome sequences, b) truncating the 3' LTR to block reverse transcription and integration of virus and/or c) replacing the gag sequence with a transdominant gag to eliminate viral release and inhibit incoming virus replication, thereby minimizing chances for recombination. Specific Aim 2. Screen the constructs in vitro to determine which construct contains the most safety modifications yet retains the expression efficacy and immunogenicity, to be used in pre-clinical and clinical studies (Project 4). Specific Aim 3. Construct the SIV counterpart of the HIV construct selected from Specific Aim 2 for evaluation in non-human primate studies (Project 3).